Safety of a Single Administration of AAV2hAQP1, an Adeno-Associated Viral Vector Encoding Human Aquaporin-1 to One Parotid Salivary Gland in People With Irradiation-Induced Parotid Salivary Hypofunction

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- Radiation can cause the parotid salivary glands to make less saliva (dry mouth). This can cause problems like infections and tooth decay. Researchers hope a new drug can help people with dry mouth caused by radiation.

Objectives:

- To examine the safety of AAV2hAQP1 gene therapy. To see if the drug increases saliva in people whose parotid glands have had radiation.

Eligibility:

- People at least 18 years of age with a history of radiation therapy for head and neck cancer.

Design:

Participants will be screened in 2 visits with:

medical history

physical exam

scans

saliva collections

sialogram. A substance is injected in the parotid gland and X-rays are taken.

non-drug infusion

IV dose of glycopyrrolate to stop saliva

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3-day hospital stay: Participants will get the gene infusion. The AAV2hAQP1 will be in a solution in a syringe. It will be slowly pushed through an opening into the gland inside your mouth.

10 outpatient visits over 3 years. These may include:

repeats of screening tests

blood and urine tests

oral and head and neck exams, including a thin scope in the airway

questionnaires

small piece of skin taken

small piece of parotid tissue taken by either: a small video-scope in the parotid duct that also takes pictures or by a small needle guided by ultrasound

scans. Participants lie in a machine or a scanner The machine may feel close to the body or face. . For some, a substance will be injected in a vein or put in the mouth.

Participants will keep a diary about how they feel before and after the therapy.

The treatment of most head and neck cancer patients includes ionizing radiation (IR). Salivary glands in the IR field suffer irreversible damage. There is no conventional treatment available to correct this condition. Our research group has been developing an adeno-associated virus vector based on the hypothesis that this vector is capable of safely transferring the human aquaporin-1 (hAQP1) cDNA gene to parotid glands of adult patients with IR-induced salivary hypofunction, resulting in an elevated salivary output. Human AQP1, the archetypal water channel, is a plasma membrane protein that facilitates water movement across lipid bilayers. Minipig studies have shown that the AAV2hAQP1 strategy for restoring salivary flow to IR-damaged salivary glands is effective without untoward effects after salivary gland delivery. As a proof of concept that AQP1 would restore saliva flow in a human population, we recently completed a phase 1 clinical trial (06-D-0206) using an Adenovirus-based vector encoding AQP1 to a single previously irradiated parotid gland in eleven patients using an open label, single dose, dose-escalation design. All patients tolerated vector delivery and study procedures well and positive objective and subjective responses were seen in five patients, all at doses <5.8 times10(9) vp/gland. At higher doses the patients possibly initiated an immune response to the vector and no improvement in gland function was observed. These findings have encouraged us to pursue studies with AAV2 based vectors, which have demonstrated lower immunogenicity and more stable expression compared with adenoviral vectors. The purpose of this clinical protocol is to test the safety of AAV2hAQP1, with some measures of efficacy, in adult patients with established IR-induced parotid gland hypofunction. The targeted tissue site for the AAV2hAQP1 vector in the proposed study is a single parotid gland. In this Phase 1 dose-escalation study, safety will be evaluated using conventional clinical and immunological parameters. The primary outcome measure for biological efficacy will be parotid gland salivary output.

Open-Label, Dose-Escalation Study Evaluating the Safety of a Single Administration of an Adeno-Associated Virus Vector Encoding Human Aquaporin-1 to One Parotid Salivary Gland in Individuals With Irradiation-Induced Parotid Salivary Hypofunction

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Layout table for eligibility information

Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA:

At least 18 years of age

History of external beam radiation therapy for head and neck cancer, with a mean dose equal to or greater than 15 Gy to a parotid gland.

Abnormal parotid gland function as judged by both absence of unstimulated parotid salivary flow and a stimulated parotid salivary flow in the targeted parotid gland >0 and <0.3 mL/min/gland after 2% citrate stimulation.

No evidence of recurrence of primary malignancy by otolaryngology (ENT) assessment. Additionally, all patients must have been disease-free of head and neck cancer for at least 5 years, a status to be determined at pre-dose screening using negative clinical exams and PET and or CT imaging of the neck and chest. The anatomic subset of HPV positive oropharyngeal cancer may be enrolled after 2 years post completion of therapy.

Willingness to practice the required birth control method ("barrier" contraception, condoms, diaphragm) until AAV2hAQP1 is no longer detectable in their serum or saliva.

Women who cannot bear children (post-menopausal or due to a surgical intervention) also will be required to practice barrier birth control methods until AAV2hAQP1 is no longer detectable in their serum or saliva.

Ability to stay at the NIH hospital for the period of time necessary to complete each on-site phase of the protocol (3-5 days).

No history of allergies to any medications or agents to be used in this protocol.

On stable medications (greater than or equal to 2 months) for any underlying medical conditions at time of vector administration.

EXCLUSION CRITERIA:

Pregnant or lactating women. Women of childbearing potential are required to have a negative serum pregnancy test at screening and a negative urine pregnancy test within 48 hours prior to gene infusion.

Any experimental therapy within 3 months.

Any active respiratory tract infection in the 3 weeks prior to day 1 of the protocol

Active infection that requires the use of intravenous antibiotics and does not resolve at least 1 week before Day 1.

Individuals, who on sialography, have a distal stenosis that would impede vector delivery.

Significant concurrent or recently diagnosed (<2 months) medical condition that, in the opinion of the Medically Responsible Investigator, could affect the patient's ability to tolerate or complete the study.

Live vaccines within 4 weeks of first infusion.

Individuals who have had an adverse response to prednisone (i.e. hallucinations).